Difficulties exist in developing safe and sterile intravenous formulations of sparingly water-soluble (i.e., water-insoluble) compounds. One such compound is 17-allylaminogeldanamycin (17-AAG) which is under development for clinical use as an anticancer agent because of it's unique mechanism of action as a modulator of HSP-90. This compound was selected for clinical studies based on its in vitro activity against chemorefractory tumor and novel biological actions. Its effect on the depletion of the erB-2 gene product p185 has been reported (Miller et al., Cancer Res., 54, 2724-30 (1994)). Another such compound is carboxyamidotriazole (CAI) which is currently under development for clinical use as an antitumor agent based on its antiangiogenic and antimetastatic effects.
Delivery systems for water-insoluble compounds have been developed using lipid vesicles and oil-in-water type emulsions (Ogawa et al., U.S. Pat. No. 5,004,756; Tabibi et al., U.S. Pat. No. 5,039,527; Cotter, U.S. Pat. No. 5,461,037; Lundquist, U.S. Pat. No. 5,660,837, Tabibi et al., U.S. Pat. No. 5,672,358). However, these formulations require complicated processing steps, and the presence of non-aqueous solvents such as dimethylsulfoxide (DMSO) causes physical instability in the formulation. For example, the complete removal of organic solvent in the processing of the liposomes has been reported to be very important to the stability of the vesicles of some systems (Vemuri et al., Acta Helvetica, 70(2), 95-111 (1995)). Other methods are said to require high-speed homogenization of the phospholipids with the active ingredient followed by complete evaporation of the organic solvent with vigorous stirring to achieve optimal entrapment of the active ingredient (Xu et al., Pharm. Research, 7(5), 553-57 (1990)). Likewise, it has been demonstrated that the addition of organic solvents to oil-in-water type emulsions causes the oil droplets to coalesce, resulting in instability (Li et al., Pharmaceutical Research, 10(4), 535-41 (1993)).
Thus, there is a need for a more satisfactory delivery system for water-insoluble drugs. The present invention provides such a drug delivery system that incorporates an organic solvent, desirably without adversely affecting the physical stability of the surfactant within the aqueous medium. The present invention also provides methods of preparing and using such a drug delivery system. These and other benefits and advantages of the present invention will be apparent from the description of the present invention herein.